Pharmaceutical tablets in divisible form containing an indentation known as a score have long been known and widely used. Problems with breaking scored tablets are well-known. These problems include loss of active drug and inaccurate division of the tablet, so that a tablet intended to be divided into two equal half-tablets often does not come close to that ideal.
Many drugs, such as warfarin, require dosage adjustments and are frequently broken. These dosage adjustments through tablet breaking by patients have been determined to be imprecise. As the following discussion demonstrates, for many years experts have called upon the pharmaceutical industry to improve the quality of tablet breaking, but limited attention has previously been paid to these calls by the pharmaceutical industry.
In 1984, Stimpel et al. (“Stimpel”), described the relative accuracy of breaking of various tablets for treatment of cardiovascular problems. M. Stimpel et al., “Breaking Tablets in Half.” The Lancet (1984):1299. Even though breaking was performed by a sophisticated, dexterous person, Stimpel found that breaking was not accurate, and opined that real world use by patients would provide yet more unsatisfactory results. Stimpel called upon the pharmaceutical industry to improve the accuracy of splitting tablets: “Clearly any assumption that halving a tablet will not lead to inaccurate doses is invalid. This potential source of inaccuracy could be even more significant in clinical situations (our study was done under ideal conditions) and the pharmaceutical industry should tackle it, either by improving divisibility (as already has been done for lopressor and logroton) or, even better, by marketing a wider range of unscored tablets to provide all the doses that might be indicated clinically.”
Despite that finding and statement, and despite the subsequent issuance of various patents relating to optimizing a scoring pattern and/or tablet shape, Rodenhuis et al., (2004) noted that: “Improving the functioning of score lines may be a more practical approach than banning this dosage form” (emphasis added). N. Rodenhuis et al., “The rationale of scored tablets as dosage form.” European J. of Pharmaceutical Sciences 21 (2004):305-308 (hereafter “Rodenhuis”). Rodenhuis observed that European regulatory authorities started a policy to discourage scoring of tablets in 1998. This policy change, according to Rodenhuis, likely related to “many recent reports of bad functioning score lines” that “many scored tablets are difficult to break,” and that “many scored tablets show unsatisfactory mass uniformity of the subdivided halves.” The authors then go on to describe useful aspects of scoring tablets. For a comprehensive review article on this topic, see van Santen, E., Barends, D. M. and Frijlink, H. W. “Breaking of scored tablets: a review” European J. of Pharmaceutics and Biopharmaceutics 53 (2002):139-145.
Some current studies that demonstrate the severity of the problem are described below. Peek et al., (2002), studied tablet splitting by “elderly patients” aged 50-79. Peek, B. T., Al-Achi, A., and Coombs, S. J. “Accuracy of Tablet Splitting by Elderly Patients,” The Journal of the American Medical Association 288 No.4 (2002):139-145. Breaking scored tablets with mechanical tablet splitters without specific instruction led to highly unsatisfactory separating of the tablets. For example, warfarin 5 mg was on average split into 1.9 and 3.1 mg tablets. This potent anticoagulant has such a narrow therapeutic range that 2, 2.5, and 3 mg tablet doses are manufactured. Biron et al., (1999), demonstrated that warfarin 10 mg also often split to less than 4.25 or greater than 5.75 mg. Biron, C., Liczner, P., Hansel, S. and Schved, J. F., “Oral Anticoagulant Drugs: Do Not Cut Tablets in Quarters.” Thromb Haemost 1201 (1999). In addition, they demonstrated that loss of mass due to crumbling or chipping from the breaking of the warfarin tablets was statistically significant. They also demonstrated that quartering of the tablets was grossly inaccurate.
McDevitt et al., (1998), found that 25 mg scored hydrochlorothiazide tablets were manually split badly enough that 12.4% deviated by more than 20% from ideal weight. McDevitt, J. T., Gurst, A. H. and Chen, Y. “Accuracy of Tablet Splitting.” Pharmacotherapy 18 No.1 (1998):193-197. 77% of the test subjects stated that they would be willing to pay a premium for individually produced 12.5 mg tablets rather than split 25 mg unscored tablets.
Rosenberg et al., (2002), studied pharmacist-dispensed split tablets. Rosenberg, J. M., Nathan, J. P. and Plakogiannis, F. “Weight Variability of Pharmacist-Dispensed Split Tablets.” Journal of American Pharmaceutical Association 42 No.2 (2002):200-205. They found that “tablet splitting resulted in an unacceptably high incidence of weight variation.” They recommended that “standards should be developed to ensure uniformity of split tablets.”
Teng et al., (2002), using a trained individual in a laboratory setting to split tablets, concluded that “the majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP (United States Pharmacopeia) uniformity test . . . The practice of dividing tablets to save costs or to improve a dosage regimen . . . is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.” Teng, J., Song, C. K., Williams, R. L. and Polli, J. E. “Lack of Medication Dose Uniformity in Commonly Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):195-199.
Rodenhuis reported that 31% of all tablets in one Netherlands study were subdivided before being swallowed. In the U.S., “managed care” insurance organizations, the Veterans Administration and others may encourage splitting by patients of unscored tablets that may not even have symmetrical shapes. Many drug products in the US either are unscored tablets, or are provided as capsules despite being able to be produced as tablets.
The invention is directed to amelioration of the problems described above. The subject invention may allow either a single agent or a mixture of two active agents (i.e., one or more drugs) to be accurately divided in halves with regard to the dose, even if the tablet does not break into equal halves by mass.
The current invention describes a tablet shape adapted for separating one vertically disposed segment from another.
In the large field of immediate release pharmaceuticals, the relative dimensions of the tablets in accordance with the subject invention are novel as applied to immediate release dosage forms. Commercially, the only product that as produced is taller than it is wide is Concerta®, which is a three-segment tablet, two of which segments are devoted to controlled release of the active drug, methylphenidate. Concerta utilizes the OROS® system, which utilizes the taller-than-wide geometry to provide a layered tablet configuration to impart controlled release characteristics. The manufacturer's directions for the use of Concerta specify that the tablets should never be broken. Except for Concerta, tablets, including those involving layers vertically disposed one on the other, have been produced wider than they are tall.
A tablet press manufacturer, Korsch AG of Germany, has developed a tablet press (the TRP 900) that can produce up to five vertically disposed layers. It has been utilized to produce taller-than-wide five-layer tablets having no active drugs therein and has also been used to manufacture Concerta.